| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To investigate the efficacy of co-administration of ramipril and indapamide SR in reduction of blood pressure in hypertensive patients whose blood pressure (BP) is not controlled by ramipril 5 mg, 10 mg or indapamide SR 1.5 mg alone. |
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| E.2.2 | Secondary objectives of the trial |
To investigate the percentage of patients whose BP is either became controlled or met the criterion of response to therapy in different treatment groups and in pools at different dosages of ramipril administered concomitantly with indapamide SR. Response to therapy is defined as the reduction in SBP/DBP at Visit 7 reaches 20/10 mmHg comparing to the baseline values.
To investigate the safety of co-administration of ramipril and indapamide SR in hypertensive patients.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Mild and moderate (Grade 1 and 2) essential hypertension not controlled at ramipril or indapamide SR monotherapy administered at least 4 weeks. Definition of not controlled mild and moderate hypertension: systolic blood pressure [SBP] ≥ 140 mmHg with or without diastolic blood pressure [DBP] ≥ 90 mmHg, but SBP ≤ 179 mmHg and DBP ≤ 109 mmHg.
2. Male and female patients ≥ 18 years, but < 80 years of age.
3. Medically accepted effective contraception for women of childbearing potential (WOCBP) and it should be continued until at least 90 days after the last dose of trial treatment).
4. Patients capable to give consent and who have signed the Informed Consent Form before any trial related assessment
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| E.4 | Principal exclusion criteria |
1. General contraindications of thiazide diuretics and/or ACE inhibitors
a) Known hypersensitivity to indapamide or other sulphonamides, ramipril or any other ACE inhibitor or to any of the excipients
b) History of angioedema (hereditary, idiopathic or due to previous angioedema with ACE inhibitors or AIIRAs)
c) Secondary hypertension
d) Extracorporeal treatments leading to contact of blood with negatively charged surfaces
e) Significant bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney
f) Renal impairment defined as eGFR < 60 ml/min
g) Hepatic encephalopathy or impairment of liver function. i.e. ASAT and/or ALAT ≥ 2 ULN, GGT ≥ 2 ULN
h) Hypokalaemia, i.e. se Potassium < LLN
i) Hyperkalaemia, i.e. se Potassium > ULN
j) Hyponatraemia i.e. se Sodium < LLN
k) Hypercalcaemia i.e. se Calcium > ULN
l) Hyperuricemia i.e. se uric acid > ULN and judged clinically significant
m) Congestive heart failure (NYHA III-IV.)
n) Type 1 or uncontrolled Type 2 diabetes mellitus, i.e. HbA1C >8%, or patients on SGLT2 inhibitor treatment.
o) Treatment with ARB, aliskiren or lithium
p) Patients with hypotensive or haemodynamically unstable states
q) Patients having a history of myocardial infarction, unstable angina pectoris, percutaneous coronary intervention, hypertensive encephalopathy, cerebrovascular accident (stroke), acute heart failure or transient ischaemic attack within the last six months
2. Any other anti-hypertensive drugs (other than ramipril and indapamide SR) used within 4 weeks prior to the screening visit.
3. Use of any enzyme-modifying drugs acting on cytochrome P450 (CYP) 3A4 enzymes via inhibition or induction within 28 days before day 1 of this trial.
4. Elderly patients < 80 years of age, but not in good physical and mental condition, who in the opinion of the Investigator will not tolerate reduction of BP until target of 140/80 mmHg (“fragile” elderly patients)
5. Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, lactose intolerance or glucose-galactose malabsorption
6. History of drug or alcohol dependency or abuse within the last 2 years
7. Concurrent alcohol and/or drug abuse.
8. Any other condition, disease or therapy which in the Investigator’s opinion would pose a risk to the subject or interfere with the trial objectives.
9. Pregnancy and lactation period. All female patients with reproductive potential must have a negative pregnancy serum test at the time of the Screening visit and have to use adequate contraception during the study.
10. Known lack of subject compliance.
11. Participation in another clinical trial within the previous 30 days.
12. Persons directly involved in the execution of this protocol and their relatives.
Females of childbearing potential must have negative serum pregnancy test at screening. (All females will be considered to be of childbearing potential unless they are postmenopausal i.e. amenorrhoeic for at least 12 consecutive months, in the appropriate age group and without other known or suspected cause or have been sterilized surgically i.e. bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing.)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is defined as a mean reduction of systolic blood pressure (SBP) after 10 weeks of treatment (measured on the last study visit before the medication is taken) compared to the baseline value (measured before the start of concomitant administration of ramipril and indapamide SR) in the treatment group the patient enrolled and irrespectively from the final therapy at the last visit. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 10 weeks of treatment(measured on the last study visit before the medication is taken) compared to the baseline value (measured before the start of concomitant administration of ramipril and indapamide SR) |
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| E.5.2 | Secondary end point(s) |
The secondary endpoints are defined as follows:
1. Mean reduction in diastolic blood pressure (DBP) after 10 weeks of treatment compared to the last DBP before the concomitant administration of ramipril and indapamide SR.
2. Mean reduction of SBP after 6 weeks of treatment compared to the last SBP before the concomitant administration of ramipril and indapamide SR.
3. Mean reduction of DBP after 6 weeks of treatment compared to the last DBP before the concomitant administration of ramipril and indapamide SR.
4. Percentage of patients whose BP is either controlled or responders (irrespectively of dose of ramipril) at Day 71 in the whole study population and in the treatment groups the patient enrolled.
5. Percentage of patients whose BP is either controlled or responders (irrespectively of dose of ramipril) at Day 99 in the whole study population and in the treatment groups the patient enrolled.
6. Percentage of patients whose BP is controlled or responders with administration of ramipril 5 mg/indapamide SR 1.5 mg and ramipril 10 mg/indapamide 1.5 mg, respectively at Day 99 in Group 1.
7. Percentage of patients whose BP is controlled with administration of ramipril 5 mg/indapamide 1.5 mg and ramipril 10 mg/indapamide 1.5 mg, respectively at Day 99 in Group 2.
8. Number of AEs reported as safety laboratory parameters out of normal range, which have clinical significance by judgement of the physician.
9. Number of Adverse events judged as related to the study treatment.
Normalization of blood pressure means systolic blood pressure [SBP] < 140 mmHg with or without diastolic blood pressure [DBP] < 90 mmHg.
However, based on the investigator’s decision, ramipril dose can be increased during the study in patients with SBP/DBP lower than 140/90 mmHg, but higher than recommended target blood pressure levels defined in the 2018 ESC/ESH Guidelines on the Management of Arterial Hypertension, who tolerate well the combination treatment.
Responder means patient has reduction in SBP/DBP reaches 20/10 mmHg comparing to the baseline values.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. after 10 weeks of treatment
2. after 6 weeks of treatment
3. after 6 weeks of treatment
4. day 71
5. day 99
6. day 99
7. day 99
8. end of study
9. end of study |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 20 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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