Hypertension
Conditions
Brief summary
Recent hypertension guidelines recommend combination therapy as initial treatment for many or most patients. Several trials suggest triple low-dose combination therapy may be highly effective in terms of achieving blood pressure control without increasing adverse effects. This trial is designed to investigate the efficacy and safety of GMRx2 in participants with high blood pressure compared to placebo.
Detailed description
TRIAL DRUG: GMRx2: single pill combination of telmisartan/amlodipine/indapamide Dose version 1: telmisartan 10 mg/amlodipine 1.25 mg/indapamide 0.625 mg Dose version 2: telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg INDICATION: Hypertension TRIAL TITLE: Efficacy and safety of GMRx2 compared to placebo for the treatment of hypertension. OBJECTIVES: To investigate the efficacy and safety of GMRx2 compared to placebo for the treatment of hypertension. INTERVENTION: A 2-week single-blind placebo run-in will be followed by a 4-week double-blind period with randomization to GMRx2 dose version 1, GMRx2 dose version 2 or placebo.
Interventions
DRUGTelmisartan 10 mg/amlodipine 1.25 mg/indapamide 0.625 mg
Oral tablets
Oral tablets
DRUGPlacebo
Placebo
Sponsors
George Medicines PTY Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
International, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 pharmacological BP-lowering treatment is not mandatory: e.g. Pooled Cohorts Equation 10-years ASCVD risk \<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 that will be stopped at this visit, OR * documentation in last 6 months of office SBP ≥ 140 mmHg and/or DBP ≥ 90mmHg on no BP lowering medicines or SBP ≥ 130 mmHg and/or DBP ≥ 85mmHg on 1 BP lowering medicine that will be stopped at this visit, OR * documentation in last 6 months of home SBP ≥ 130 mmHg and/or DBP ≥ 80mmHg on no BP lowering medicines or SBP ≥ 120 mmHg and/or DBP ≥ 75mmHg on 1 BP lowering medicine 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 BP lowering medicine that will be stopped at this visit 5. No contraindication to trial medications, including 2-weeks placebo run-in and 4-weeks randomized treatment period with GMRx2 (dose version 1 or 2) or placebo. At randomization visit: 1. Home seated mean SBP 130-154 mmHg in the week before the randomization visit. 2. Adherence of 80-120% to placebo run-in. 3. Tolerated placebo run-in. 4. Adherence to home BP monitoring schedule: in the week before randomization, at least 6 measures (e.g. ≥2 sets of triplicate 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 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 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 any of 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 heart failure. 9. Current/history of a known secondary cause of hypertension, such as primary aldosteronism, renal artery stenosis, pheochromocytoma, or Cushing's syndrome. 10. Current/history of substantially uncontrolled diabetes (HbA1c \> 11.0%) within last three months. 11. Current/history of end-stage renal disease or anuria or estimated glomerular filtration 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 the judgment of the investigator could interfere with the effective conduct of the trial or 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 accurate measurement of BP. 15. Currently taking or might need during the trial, a concomitant treatment which is known to interact significantly with the trial medication: digoxin, lithium, diabetics receiving 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: other antihypertensive drugs, endothelin receptor antagonists, neprilysin inhibitors, or other 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 major gastrointestinal tract surgery (e.g. gastrectomy, lap band, or bowel resection) or acute 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: 1. Unable to adhere to the trial procedures during the run-in 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/low in clinic only; for example the clinical relevance of 'whitecoat hypertension' is uncertain. 2. 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 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in Change in Home Seated Mean Systolic Blood Pressure (SBP) From Randomization to Week 4 | Randomization to Week 4 | Each blood pressure (BP) measurement consisted of valid SBP values (ie. SBP\>60 mmHg and \<250 mmHg). BP values were summarized using descriptive statistics, including actual values and changes from randomization to Week 4, by timepoint and treatment groups. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Difference in Change in Clinic Seated Mean Diastolic Blood Pressure (DBP) From Randomization to Week 4 | Randomization to Week 4 | Each blood pressure (BP) measurement consisted of valid DBP values (ie. DBP\>40mmHg and \<150mmHg). BP values were summarized using descriptive statistics, including actual values and changes from randomization to Week 4, by timepoint and treatment groups. |
| Percentage of Participants With Clinic Seated Mean Systolic Blood Pressure (SBP) <140 and DBP <90 mmHg at Week 4 | At Week 4 | The percentage of participants achieving averaged clinic SBP \<140 and DBP \<90 mmHg at Week 4 was evaluated. |
| Percentage of Participants With Clinic Seated Mean Systolic Blood Pressure (SBP) <130 and Diastolic Blood Pressure (DBP) <80 mmHg at Week 4 | At Week 4 | The percentage of participants achieving averaged clinic SBP \<130 and DBP \<80 mmHg at Week 4 was evaluated. Participants were analyzed in the treatment group to which they have been randomized. |
| Difference in Change in Home Seated Mean Diastolic Blood Pressure (DBP) From Randomization to Week 4 | Randomization to Week 4 | Each blood pressure (BP) measurement consisted of valid DBP values (ie. DBP\>40mmHg and \<150mmHg). BP values were summarized using descriptive statistics, including actual values and changes from randomization to Week 4, by timepoint and treatment groups. To evaluate the difference in change, least squares mean change value is reported. |
| Difference in Change in Clinic Seated Mean Mean Systolic Blood Pressure (SBP) From Randomization to Week 4 | Randomization to Week 4 | Each blood pressure (BP) measurement consisted of valid SBP values (ie. SBP\>60 mmHg and \<250 mmHg). BP values were summarized using descriptive statistics, including actual values and changes from randomization to Week 4, by timepoint and treatment groups. |
| Difference in Change in Trough Home Seated Mean Diastolic Blood Pressure (DBP) From Randomization to Week 4 | Randomization to Week 4 | Difference in change in trough home DBP for GMRx2 vs placebo was evaluated at Week 4. Trough values were measured before morning dose of the study medication. To evaluate the difference in change, least squares mean change value is reported. |
| Percentage of Participants With Home Seated Mean Systolic Blood Pressure (SBP) <135 and Diastolic Blood Pressure (DBP) <85 mmHg at Week 4 | At Week 4 | The percentage of participants achieving home seated mean SBP \<135 and DBP \<85 mmHg at Week 4 was evaluated |
| Percentage of Participants With Home Seated Mean Systolic Blood Pressure (SBP) <130 and Diastolic Blood Pressure (DBP) <80 mmHg at Week 4 | Randomization to Week 4 | The percentage of participants achieving averaged home seated mean SBP \<130 and DBP \<80 mmHg at Week 4 was evaluated |
| Difference in Change in Trough Home Seated Mean Systolic Blood Pressure (SBP) From Randomization to Week 4 | Randomization to Week 4 | Difference in change in trough home SBP for GMRx2 vs placebo was evaluated at Week 4. Trough values were measured before morning dose of the study medication. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Discontinued Trial Medication Due to Adverse Event (AE) or a Serious Adverse Event (SAE) From Randomization to Week 4 | Randomization to Week 4 | The primary safety outcome is percentage of participants discontinued trial medication due to an Adverse Event (AE) or a Serious Adverse Event (SAE) from randomization to Week 4. |
| Percentage of Participants With Postural Hypertension at Week 4 | At Week 4 | The secondary safety outcome is percentage of participants with postural hypertension at Week 4 |
| Percentage of Participants With an Serious Adverse Event (SAE) From Randomization to Week 4 | Randomization to Week 4 | The secondary outcome is percentage of participants with an SAE from randomization to Week 4 |
| Percentage of Participants With Symptomatic Hypotension From Randomization to Week 4 | Randomization to Week 4 | The Secondary Safety Outcome is percentage of participants with symptomatic hypotension from randomization to Week 4 |
| Percentage of Participants With Serum Sodium Concentration Below 135 mmol/l at Week 4 | At Week 4 | The Secondary safety outcome is percentage of participants with serum sodium concentration below 135 mmol/l at Week 4 |
| Percentage of Participants With Serum Sodium Concentration Above 145 mmol/l at Week 4 | At Week 4 | The Secondary safety outcome is percentage of participants with serum sodium concentration above 145 mmol/l at Week 4 |
| The Percentage of Participants With Serum Potassium Concentration Below 3.5 mmol/l at Week 4 | At Week 4 | The secondary safety outcome is percentage of participants with serum potassium concentration below 3.5 mmol/l at Week 4 |
| Percentage of Participants With Serum Potassium Concentration Above 5.5 mmol/l at Week 4 | At Week 4 | The secondary safety outcome is percentage of participants with serum potassium concentration above 5.5 mmol/l at Week 4. |
| Percentage of Participants With eGFR Drop of Over 30% From Randomization to Week 4 | Randomization to Week 4 | The secondary safety outcome is percentage of participants with eGFR drop of over 30% from randomization to Week 4 |
| Percentage of Participants With Serum Sodium <135mmol/l or >145 mmol/l, and/or Serum Potassium <3.5 mmol/l or >5.5mmol/l at Week 4 | At Week 4 | The secondary safety outcome is percentage of participants with serum sodium \<135mmol/l or \>145 mmol/l, and/or serum potassium \<3.5 mmol/l or \>5.5mmol/l at Week 4 |
| Percentage of Participants With Postural Hypotension at Week 4 | At Week 4 | The secondary safety outcome percentage of participants with postural hypotension at Week 4 |
Countries
Australia, Nigeria, Sri Lanka, United Kingdom, United States
Participant flow
Recruitment details
The trial was conducted at 47 trial centers spread across 5 countries (United States of America \[USA\] 23, Great Britain 10, Sri Lanka 7, Australia 5, and Nigeria 2).
Pre-assignment details
Out of 1584 participants screened, 755 participants entered the 2-week single-blind placebo run-in period. Overall, 460 of the 755 participants who entered the run-in period were not randomized, the most common reason was failure to meet the criteria of home seated mean SBP of 130-154 mmHg in the week prior to the randomization visit. Total of 295 participants were randomized to the treatment groups at the end of run-in period.
Participants by arm
| Arm | Count |
|---|---|
| Triple ¼ (GMRx2) Telmisartan 10 mg/amlodipine 1.25 mg/indapamide 0.625 mg
Telmisartan 10 mg/amlodipine 1.25 mg/indapamide 0.625 mg: Oral tablets
Over encapsulated Telmisartan 10 mg/amlodipine 1.25 mg/indapamide 0.625 mg oral tablet once daily in the morning after home blood pressure (BP) measurement from week 1 to week 4 | 113 |
| Triple ½ (GMRx2) Telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg
Telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg: Oral tablets
Over encapsulated Telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg oral tablet once daily in the morning after home BP measurement from week 1 to week 4 | 119 |
| Placebo Placebo
Placebo: Placebo
One tablet daily in the morning after home BP measurement from week 1 to week 4. | 63 |
| Total | 295 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-Blind Period | Adverse Event | 0 | 2 | 2 |
| Double-Blind Period | Lost to Follow-up | 1 | 2 | 2 |
| Double-Blind Period | Missing | 0 | 1 | 0 |
| Double-Blind Period | Other | 0 | 2 | 0 |
| Double-Blind Period | Participant moved to open-label extension (OLE) study | 21 | 21 | 8 |
| Double-Blind Period | Run in failure | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Triple ¼ (GMRx2) | Triple ½ (GMRx2) | Placebo |
|---|---|---|---|---|
| Age, Continuous | 50.5 years STANDARD_DEVIATION 11.47 | 49.5 years STANDARD_DEVIATION 12.25 | 51.2 years STANDARD_DEVIATION 9.88 | 50.9 years STANDARD_DEVIATION 12.81 |
| Alcohol consumption - Currently drink alcohol once a week or more | 113 Participants | 38 Participants | 50 Participants | 25 Participants |
| BMI | 30.5 kg/m^2 STANDARD_DEVIATION 6.22 | 30.9 kg/m^2 STANDARD_DEVIATION 6.04 | 30.4 kg/m^2 STANDARD_DEVIATION 6.69 | 30.0 kg/m^2 STANDARD_DEVIATION 5.67 |
| Education - No formal education | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Education - Primary school | 20 Participants | 7 Participants | 8 Participants | 5 Participants |
| Education - Secondary school | 85 Participants | 33 Participants | 39 Participants | 13 Participants |
| Education - Tertiary school | 148 Participants | 52 Participants | 57 Participants | 39 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 105 Participants | 40 Participants | 42 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 184 Participants | 70 Participants | 76 Participants | 38 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 3 Participants | 1 Participants | 2 Participants |
| Height | 166.55 cm STANDARD_DEVIATION 10.223 | 165.97 cm STANDARD_DEVIATION 10.439 | 166.68 cm STANDARD_DEVIATION 10.247 | 167.36 cm STANDARD_DEVIATION 9.878 |
| Pre-screening 12-lead ECG - Any other abnormalities | 78 Participants | 30 Participants | 32 Participants | 16 Participants |
| Pre-screening 12-lead ECG - Normal | 217 Participants | 83 Participants | 87 Participants | 47 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 61 Participants | 26 Participants | 27 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 49 Participants | 18 Participants | 20 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 181 Participants | 66 Participants | 72 Participants | 43 Participants |
| Region of Enrollment Australia | 42 Participants | 15 Participants | 16 Participants | 11 Participants |
| Region of Enrollment Nigeria | 10 Participants | 2 Participants | 5 Participants | 3 Participants |
| Region of Enrollment Sri Lanka | 43 Participants | 19 Participants | 18 Participants | 6 Participants |
| Region of Enrollment United Kingdom | 43 Participants | 18 Participants | 15 Participants | 10 Participants |
| Region of Enrollment United States | 157 Participants | 59 Participants | 65 Participants | 33 Participants |
| Sex: Female, Male Female | 165 Participants | 68 Participants | 61 Participants | 36 Participants |
| Sex: Female, Male Male | 130 Participants | 45 Participants | 58 Participants | 27 Participants |
| Smoking - Current smoker | 24 Participants | 8 Participants | 12 Participants | 4 Participants |
| Smoking - Ex-smoker | 55 Participants | 15 Participants | 28 Participants | 12 Participants |
| Smoking - Never | 216 Participants | 90 Participants | 79 Participants | 47 Participants |
| Vocational training | 41 Participants | 21 Participants | 15 Participants | 5 Participants |
| Weight | 85.22 kg STANDARD_DEVIATION 21.319 | 85.50 kg STANDARD_DEVIATION 20.865 | 85.12 kg STANDARD_DEVIATION 22.419 | 84.92 kg STANDARD_DEVIATION 20.299 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 113 | 0 / 119 | 0 / 63 | 0 / 460 |
| other Total, other adverse events | 25 / 113 | 32 / 119 | 10 / 63 | 17 / 460 |
| serious Total, serious adverse events | 0 / 113 | 3 / 119 | 2 / 63 | 2 / 460 |
Outcome results
Primary
Difference in Change in Home Seated Mean Systolic Blood Pressure (SBP) From Randomization to Week 4
Each blood pressure (BP) measurement consisted of valid SBP values (ie. SBP\>60 mmHg and \<250 mmHg). BP values were summarized using descriptive statistics, including actual values and changes from randomization to Week 4, by timepoint and treatment groups.
Time frame: Randomization to Week 4
Population: Analysis was performed on randomized set (All participants who have been randomized). Participants were analyzed in the treatment group to which they have been randomized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Triple ¼ (GMRx2) | Difference in Change in Home Seated Mean Systolic Blood Pressure (SBP) From Randomization to Week 4 | -9.6 mmHg | Standard Error 1 |
| Triple ½ (GMRx2) | Difference in Change in Home Seated Mean Systolic Blood Pressure (SBP) From Randomization to Week 4 | -10.4 mmHg | Standard Error 1.33 |
| Placebo | Difference in Change in Home Seated Mean Systolic Blood Pressure (SBP) From Randomization to Week 4 | -2.2 mmHg | Standard Error 1.16 |
Comparison: The analysis was performed using a mixed model for repeated measures (MMRM) for estimating the difference between Triple ¼ GMRx2 and placebo at Week 4p-value: <0.000195% CI: [-10.176, -4.486]MIANALYZE procedure
Comparison: The analysis was performed using a mixed model for repeated measures (MMRM) for estimating the difference between Triple ½ GMRx2 and placebo at Week 4p-value: <0.000195% CI: [-11.305, -5.151]MIANALYZE procedure
Secondary
Difference in Change in Clinic Seated Mean Diastolic Blood Pressure (DBP) From Randomization to Week 4
Each blood pressure (BP) measurement consisted of valid DBP values (ie. DBP\>40mmHg and \<150mmHg). BP values were summarized using descriptive statistics, including actual values and changes from randomization to Week 4, by timepoint and treatment groups.
Time frame: Randomization to Week 4
Population: Analysis was performed on randomized set (All participants who have been randomized). Participants were analyzed in the treatment group to which they have been randomized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Triple ¼ (GMRx2) | Difference in Change in Clinic Seated Mean Diastolic Blood Pressure (DBP) From Randomization to Week 4 | -3.5 mmHg | Standard Error 0.6 |
| Triple ½ (GMRx2) | Difference in Change in Clinic Seated Mean Diastolic Blood Pressure (DBP) From Randomization to Week 4 | -4.3 mmHg | Standard Error 0.93 |
| Placebo | Difference in Change in Clinic Seated Mean Diastolic Blood Pressure (DBP) From Randomization to Week 4 | 0.5 mmHg | Standard Error 0.91 |
p-value: 0.001595% CI: [-6.413, -1.597]MMRM procedure
p-value: <0.000195% CI: [-7.13, -2.595]MMRM procedure
Secondary
Difference in Change in Clinic Seated Mean Mean Systolic Blood Pressure (SBP) From Randomization to Week 4
Each blood pressure (BP) measurement consisted of valid SBP values (ie. SBP\>60 mmHg and \<250 mmHg). BP values were summarized using descriptive statistics, including actual values and changes from randomization to Week 4, by timepoint and treatment groups.
Time frame: Randomization to Week 4
Population: Analysis was performed on randomized set (All participants who have been randomized). Participants were analyzed in the treatment group to which they have been randomized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Triple ¼ (GMRx2) | Difference in Change in Clinic Seated Mean Mean Systolic Blood Pressure (SBP) From Randomization to Week 4 | -6.6 mmHg | Standard Error 0.94 |
| Triple ½ (GMRx2) | Difference in Change in Clinic Seated Mean Mean Systolic Blood Pressure (SBP) From Randomization to Week 4 | -8.2 mmHg | Standard Error 1.25 |
| Placebo | Difference in Change in Clinic Seated Mean Mean Systolic Blood Pressure (SBP) From Randomization to Week 4 | 1.3 mmHg | Standard Error 1.19 |
p-value: <0.000195% CI: [-11.281, -4.681]MMRM procedure
p-value: <0.000195% CI: [-13.588, 5.449]MMRM procedure
Secondary
Difference in Change in Home Seated Mean Diastolic Blood Pressure (DBP) From Randomization to Week 4
Each blood pressure (BP) measurement consisted of valid DBP values (ie. DBP\>40mmHg and \<150mmHg). BP values were summarized using descriptive statistics, including actual values and changes from randomization to Week 4, by timepoint and treatment groups. To evaluate the difference in change, least squares mean change value is reported.
Time frame: Randomization to Week 4
Population: Analysis was performed on randomized set (All participants who have been randomized). Participants were analyzed in the treatment group to which they have been randomized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Triple ¼ (GMRx2) | Difference in Change in Home Seated Mean Diastolic Blood Pressure (DBP) From Randomization to Week 4 | -5.1 mmHg | Standard Error 0.76 |
| Triple ½ (GMRx2) | Difference in Change in Home Seated Mean Diastolic Blood Pressure (DBP) From Randomization to Week 4 | -6.6 mmHg | Standard Error 0.6 |
| Placebo | Difference in Change in Home Seated Mean Diastolic Blood Pressure (DBP) From Randomization to Week 4 | -1.1 mmHg | Standard Error 0.79 |
p-value: 0.000295% CI: [-5.978, -2.013]MMRM procedure
p-value: <0.000195% CI: [-7.328, -3.694]MMRM procedure
Secondary
Difference in Change in Trough Home Seated Mean Diastolic Blood Pressure (DBP) From Randomization to Week 4
Difference in change in trough home DBP for GMRx2 vs placebo was evaluated at Week 4. Trough values were measured before morning dose of the study medication. To evaluate the difference in change, least squares mean change value is reported.
Time frame: Randomization to Week 4
Population: Analysis was performed on randomized set (All participants who have been randomized). Participants were analyzed in the treatment group to which they have been randomized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Triple ¼ (GMRx2) | Difference in Change in Trough Home Seated Mean Diastolic Blood Pressure (DBP) From Randomization to Week 4 | -4.2 mmHg | Standard Error 0.83 |
| Triple ½ (GMRx2) | Difference in Change in Trough Home Seated Mean Diastolic Blood Pressure (DBP) From Randomization to Week 4 | -5.7 mmHg | Standard Error 0.65 |
| Placebo | Difference in Change in Trough Home Seated Mean Diastolic Blood Pressure (DBP) From Randomization to Week 4 | -0.3 mmHg | Standard Error 0.93 |
Comparison: The difference between Triple ¼ GMRx2 Dose and placebo at Week 4 was estimated using MMRMp-value: 0.000395% CI: [-5.865, -1.847]MMRM procedure
Comparison: The difference between Triple ½ GMRx2 Dose and placebo at Week 4 was estimated using MMRMp-value: <0.000195% CI: [-7.915, -2.932]MMRM procedure
Secondary
Difference in Change in Trough Home Seated Mean Systolic Blood Pressure (SBP) From Randomization to Week 4
Difference in change in trough home SBP for GMRx2 vs placebo was evaluated at Week 4. Trough values were measured before morning dose of the study medication.
Time frame: Randomization to Week 4
Population: Analysis was performed on randomized set (All participants who have been randomized). Participants were analyzed in the treatment group to which they have been randomized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Triple ¼ (GMRx2) | Difference in Change in Trough Home Seated Mean Systolic Blood Pressure (SBP) From Randomization to Week 4 | -8.1 mmHg | Standard Error 1.24 |
| Triple ½ (GMRx2) | Difference in Change in Trough Home Seated Mean Systolic Blood Pressure (SBP) From Randomization to Week 4 | -10.1 mmHg | Standard Error 1.36 |
| Placebo | Difference in Change in Trough Home Seated Mean Systolic Blood Pressure (SBP) From Randomization to Week 4 | -1.3 mmHg | Standard Error 1.24 |
Comparison: The difference between Triple ¼ GMRx2 Dose and placebo at Week 4 was estimated using MMRMp-value: 0.000395% CI: [-10.3, -3.287]MMRM procedure
Comparison: The difference between Triple ½ GMRx2 Dose and placebo at Week 4 was estimated using MMRMp-value: <0.000195% CI: [-12.403, -5.082]MMRM procedure
Secondary
Percentage of Participants With Clinic Seated Mean Systolic Blood Pressure (SBP) <130 and Diastolic Blood Pressure (DBP) <80 mmHg at Week 4
The percentage of participants achieving averaged clinic SBP \<130 and DBP \<80 mmHg at Week 4 was evaluated. Participants were analyzed in the treatment group to which they have been randomized.
Time frame: At Week 4
Population: Analysis was performed on randomized set (All participants who have been randomized). Participants were analyzed in the treatment group to which they have been randomized.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Triple ¼ (GMRx2) | Percentage of Participants With Clinic Seated Mean Systolic Blood Pressure (SBP) <130 and Diastolic Blood Pressure (DBP) <80 mmHg at Week 4 | 23 Participants |
| Triple ½ (GMRx2) | Percentage of Participants With Clinic Seated Mean Systolic Blood Pressure (SBP) <130 and Diastolic Blood Pressure (DBP) <80 mmHg at Week 4 | 36 Participants |
| Placebo | Percentage of Participants With Clinic Seated Mean Systolic Blood Pressure (SBP) <130 and Diastolic Blood Pressure (DBP) <80 mmHg at Week 4 | 2 Participants |
Comparison: Percentages were calculated from the total number of participants within the randomized set.p-value: <0.000195% CI: [6.07, 26.385]Wald test
Comparison: Percentages were calculated from the total number of participants within the randomized setp-value: <0.000195% CI: [15.237, 36.646]Wald test
Secondary
Percentage of Participants With Clinic Seated Mean Systolic Blood Pressure (SBP) <140 and DBP <90 mmHg at Week 4
The percentage of participants achieving averaged clinic SBP \<140 and DBP \<90 mmHg at Week 4 was evaluated.
Time frame: At Week 4
Population: Analysis was performed on randomized set (All participants who have been randomized). Participants were analyzed in the treatment group to which they have been randomized.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Triple ¼ (GMRx2) | Percentage of Participants With Clinic Seated Mean Systolic Blood Pressure (SBP) <140 and DBP <90 mmHg at Week 4 | 73 Participants |
| Triple ½ (GMRx2) | Percentage of Participants With Clinic Seated Mean Systolic Blood Pressure (SBP) <140 and DBP <90 mmHg at Week 4 | 83 Participants |
| Placebo | Percentage of Participants With Clinic Seated Mean Systolic Blood Pressure (SBP) <140 and DBP <90 mmHg at Week 4 | 23 Participants |
p-value: 0.000295% CI: [11.811, 42.45]Wald test
p-value: <0.000195% CI: [17.199, 47.186]Wald test
Secondary
Percentage of Participants With Home Seated Mean Systolic Blood Pressure (SBP) <130 and Diastolic Blood Pressure (DBP) <80 mmHg at Week 4
The percentage of participants achieving averaged home seated mean SBP \<130 and DBP \<80 mmHg at Week 4 was evaluated
Time frame: Randomization to Week 4
Population: Analysis was performed on randomized set (All participants who have been randomized). Participants were analyzed in the treatment group to which they have been randomized.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Triple ¼ (GMRx2) | Percentage of Participants With Home Seated Mean Systolic Blood Pressure (SBP) <130 and Diastolic Blood Pressure (DBP) <80 mmHg at Week 4 | 32 Participants |
| Triple ½ (GMRx2) | Percentage of Participants With Home Seated Mean Systolic Blood Pressure (SBP) <130 and Diastolic Blood Pressure (DBP) <80 mmHg at Week 4 | 40 Participants |
| Placebo | Percentage of Participants With Home Seated Mean Systolic Blood Pressure (SBP) <130 and Diastolic Blood Pressure (DBP) <80 mmHg at Week 4 | 7 Participants |
p-value: 0.00395% CI: [3.637, 28.424]Wald test
p-value: <0.000195% CI: [8.72, 33.665]Wald test
Secondary
Percentage of Participants With Home Seated Mean Systolic Blood Pressure (SBP) <135 and Diastolic Blood Pressure (DBP) <85 mmHg at Week 4
The percentage of participants achieving home seated mean SBP \<135 and DBP \<85 mmHg at Week 4 was evaluated
Time frame: At Week 4
Population: Analysis was performed on randomized set (All participants who have been randomized). Participants were analyzed in the treatment group to which they have been randomized.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Triple ¼ (GMRx2) | Percentage of Participants With Home Seated Mean Systolic Blood Pressure (SBP) <135 and Diastolic Blood Pressure (DBP) <85 mmHg at Week 4 | 67 Participants |
| Triple ½ (GMRx2) | Percentage of Participants With Home Seated Mean Systolic Blood Pressure (SBP) <135 and Diastolic Blood Pressure (DBP) <85 mmHg at Week 4 | 64 Participants |
| Placebo | Percentage of Participants With Home Seated Mean Systolic Blood Pressure (SBP) <135 and Diastolic Blood Pressure (DBP) <85 mmHg at Week 4 | 15 Participants |
p-value: <0.000195% CI: [19.541, 48.549]Wald test
p-value: <0.000195% CI: [14.218, 43.093]Wald test
Other Pre-specified
Percentage of Participants Discontinued Trial Medication Due to Adverse Event (AE) or a Serious Adverse Event (SAE) From Randomization to Week 4
The primary safety outcome is percentage of participants discontinued trial medication due to an Adverse Event (AE) or a Serious Adverse Event (SAE) from randomization to Week 4.
Time frame: Randomization to Week 4
Population: Analysis was done on safety population. The Safety Set is defined as all participants who took at least one dose of study treatment, including during Period 1 single-blind run-in. For the analysis of the safety endpoints, participants were analyzed in the treatment group they actually received. One participant each from Triple ½ (GMRx2) and Placebo group did not receive randomly assigned treatment during Randomization to Week 4 period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Triple ¼ (GMRx2) | Percentage of Participants Discontinued Trial Medication Due to Adverse Event (AE) or a Serious Adverse Event (SAE) From Randomization to Week 4 | 0 Participants |
| Triple ½ (GMRx2) | Percentage of Participants Discontinued Trial Medication Due to Adverse Event (AE) or a Serious Adverse Event (SAE) From Randomization to Week 4 | 6 Participants |
| Placebo | Percentage of Participants Discontinued Trial Medication Due to Adverse Event (AE) or a Serious Adverse Event (SAE) From Randomization to Week 4 | 1 Participants |
95% CI: [-9.83, 2.76]
95% CI: [-5.276, 9.774]
Other Pre-specified
Percentage of Participants With an Serious Adverse Event (SAE) From Randomization to Week 4
The secondary outcome is percentage of participants with an SAE from randomization to Week 4
Time frame: Randomization to Week 4
Population: Analysis was done on safety population. The Safety Set is defined as all participants who took at least one dose of study treatment, including during Period 1 single-blind run-in. For the analysis of the safety endpoints, participants were analyzed in the treatment group they actually received. One participant each from Triple ½ (GMRx2) and Placebo group did not receive randomly assigned treatment during Randomization to Week 4 period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Triple ¼ (GMRx2) | Percentage of Participants With an Serious Adverse Event (SAE) From Randomization to Week 4 | 0 Participants |
| Triple ½ (GMRx2) | Percentage of Participants With an Serious Adverse Event (SAE) From Randomization to Week 4 | 2 Participants |
| Placebo | Percentage of Participants With an Serious Adverse Event (SAE) From Randomization to Week 4 | 2 Participants |
95% CI: [-12.171, 1.662]
95% CI: [-10.585, 4.049]
Other Pre-specified
Percentage of Participants With eGFR Drop of Over 30% From Randomization to Week 4
The secondary safety outcome is percentage of participants with eGFR drop of over 30% from randomization to Week 4
Time frame: Randomization to Week 4
Population: The analysis of binary secondary safety endpoints was performed on the Safety Analysis Set, limited to those participants who were randomized.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Triple ¼ (GMRx2) | Percentage of Participants With eGFR Drop of Over 30% From Randomization to Week 4 | 0 Participants |
| Triple ½ (GMRx2) | Percentage of Participants With eGFR Drop of Over 30% From Randomization to Week 4 | 0 Participants |
| Placebo | Percentage of Participants With eGFR Drop of Over 30% From Randomization to Week 4 | 1 Participants |
95% CI: [-9.684, 2.778]
95% CI: [-9.684, 2.59]
Other Pre-specified
Percentage of Participants With Postural Hypertension at Week 4
The secondary safety outcome is percentage of participants with postural hypertension at Week 4
Time frame: At Week 4
Population: The analysis of binary secondary safety endpoints was performed on the Safety Analysis Set, limited to those participants who were randomized.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Triple ¼ (GMRx2) | Percentage of Participants With Postural Hypertension at Week 4 | 19 Participants |
| Triple ½ (GMRx2) | Percentage of Participants With Postural Hypertension at Week 4 | 31 Participants |
| Placebo | Percentage of Participants With Postural Hypertension at Week 4 | 13 Participants |
p-value: <0.000195% CI: [-17.664, 8.366]GEE procedure
p-value: <0.000195% CI: [-9.04, 17.981]GEE procedure
Other Pre-specified
Percentage of Participants With Postural Hypotension at Week 4
The secondary safety outcome percentage of participants with postural hypotension at Week 4
Time frame: At Week 4
Population: The analysis of binary secondary safety endpoints was performed on the Safety Analysis Set, limited to those participants who were randomized.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Triple ¼ (GMRx2) | Percentage of Participants With Postural Hypotension at Week 4 | 7 Participants |
| Triple ½ (GMRx2) | Percentage of Participants With Postural Hypotension at Week 4 | 4 Participants |
| Placebo | Percentage of Participants With Postural Hypotension at Week 4 | 3 Participants |
95% CI: [-8.585, 8.916]
95% CI: [-11.077, 5.161]
Other Pre-specified
Percentage of Participants With Serum Potassium Concentration Above 5.5 mmol/l at Week 4
The secondary safety outcome is percentage of participants with serum potassium concentration above 5.5 mmol/l at Week 4.
Time frame: At Week 4
Population: The analysis of binary secondary safety endpoints was performed on the Safety Analysis Set, limited to those participants who were randomized.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Triple ¼ (GMRx2) | Percentage of Participants With Serum Potassium Concentration Above 5.5 mmol/l at Week 4 | 1 Participants |
| Triple ½ (GMRx2) | Percentage of Participants With Serum Potassium Concentration Above 5.5 mmol/l at Week 4 | 0 Participants |
| Placebo | Percentage of Participants With Serum Potassium Concentration Above 5.5 mmol/l at Week 4 | 0 Participants |
95% CI: [-6.324, 5.548]
95% CI: [0, 3.05]
Other Pre-specified
Percentage of Participants With Serum Sodium <135mmol/l or >145 mmol/l, and/or Serum Potassium <3.5 mmol/l or >5.5mmol/l at Week 4
The secondary safety outcome is percentage of participants with serum sodium \<135mmol/l or \>145 mmol/l, and/or serum potassium \<3.5 mmol/l or \>5.5mmol/l at Week 4
Time frame: At Week 4
Population: The analysis of binary secondary safety endpoints was performed on the Safety Analysis Set, limited to those participants who were randomized.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Triple ¼ (GMRx2) | Percentage of Participants With Serum Sodium <135mmol/l or >145 mmol/l, and/or Serum Potassium <3.5 mmol/l or >5.5mmol/l at Week 4 | 12 Participants |
| Triple ½ (GMRx2) | Percentage of Participants With Serum Sodium <135mmol/l or >145 mmol/l, and/or Serum Potassium <3.5 mmol/l or >5.5mmol/l at Week 4 | 12 Participants |
| Placebo | Percentage of Participants With Serum Sodium <135mmol/l or >145 mmol/l, and/or Serum Potassium <3.5 mmol/l or >5.5mmol/l at Week 4 | 4 Participants |
95% CI: [-6.722, 12.959]
95% CI: [-7.158, 12.133]
Other Pre-specified
Percentage of Participants With Serum Sodium Concentration Above 145 mmol/l at Week 4
The Secondary safety outcome is percentage of participants with serum sodium concentration above 145 mmol/l at Week 4
Time frame: At Week 4
Population: The analysis of binary secondary safety endpoints was performed on the Safety Analysis Set, limited to those participants who were randomized.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Triple ¼ (GMRx2) | Percentage of Participants With Serum Sodium Concentration Above 145 mmol/l at Week 4 | 4 Participants |
| Triple ½ (GMRx2) | Percentage of Participants With Serum Sodium Concentration Above 145 mmol/l at Week 4 | 5 Participants |
| Placebo | Percentage of Participants With Serum Sodium Concentration Above 145 mmol/l at Week 4 | 3 Participants |
95% CI: [-10.928, 5.573]
95% CI: [1.38, 9.53]
Other Pre-specified
Percentage of Participants With Serum Sodium Concentration Below 135 mmol/l at Week 4
The Secondary safety outcome is percentage of participants with serum sodium concentration below 135 mmol/l at Week 4
Time frame: At Week 4
Population: The analysis of binary secondary safety endpoints was performed on the Safety Analysis Set, limited to those participants who were randomized.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Triple ¼ (GMRx2) | Percentage of Participants With Serum Sodium Concentration Below 135 mmol/l at Week 4 | 4 Participants |
| Triple ½ (GMRx2) | Percentage of Participants With Serum Sodium Concentration Below 135 mmol/l at Week 4 | 1 Participants |
| Placebo | Percentage of Participants With Serum Sodium Concentration Below 135 mmol/l at Week 4 | 0 Participants |
95% CI: [-4.012, 9.35]
95% CI: [-6.364, 5.278]
Other Pre-specified
Percentage of Participants With Symptomatic Hypotension From Randomization to Week 4
The Secondary Safety Outcome is percentage of participants with symptomatic hypotension from randomization to Week 4
Time frame: Randomization to Week 4
Population: Analysis was done on safety population. The Safety Set is defined as all participants who took at least one dose of study treatment, including during Period 1 single-blind run-in. For the analysis of the safety endpoints, participants were analyzed in the treatment group they actually received. One participant each from Triple ½ (GMRx2) and Placebo group did not receive randomly assigned treatment during Randomization to Week 4 period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Triple ¼ (GMRx2) | Percentage of Participants With Symptomatic Hypotension From Randomization to Week 4 | 4 Participants |
| Triple ½ (GMRx2) | Percentage of Participants With Symptomatic Hypotension From Randomization to Week 4 | 6 Participants |
| Placebo | Percentage of Participants With Symptomatic Hypotension From Randomization to Week 4 | 0 Participants |
95% CI: [-4.115, 9.352]
95% CI: [-2.779, 11.2]
Other Pre-specified
The Percentage of Participants With Serum Potassium Concentration Below 3.5 mmol/l at Week 4
The secondary safety outcome is percentage of participants with serum potassium concentration below 3.5 mmol/l at Week 4
Time frame: At Week 4
Population: The analysis of binary secondary safety endpoints was performed on the Safety Analysis Set, limited to those participants who were randomized.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Triple ¼ (GMRx2) | The Percentage of Participants With Serum Potassium Concentration Below 3.5 mmol/l at Week 4 | 4 Participants |
| Triple ½ (GMRx2) | The Percentage of Participants With Serum Potassium Concentration Below 3.5 mmol/l at Week 4 | 6 Participants |
| Placebo | The Percentage of Participants With Serum Potassium Concentration Below 3.5 mmol/l at Week 4 | 1 Participants |
95% CI: [-6.492, 7.954]
95% CI: [-5.171, 9.704]