| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 13.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10015488 |
| E.1.2 | Term | Essential hypertension |
| E.1.2 | System Organ Class | 10047065 - Vascular disorders |
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| 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 evaluate the efficacy of 4 doses of AHU377 given once daily (50mg,100mg, 200mg and 400mg ) when given in combination with valsartan 320mg in patients with essential hypertension by testing the hypothesis that the reduction in mean sitting systolic blood pressure (msSBP) exhibits a dose response as compared to valsartan 320 mg monotherapy after 8 weeks of treatment. |
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| E.2.2 | Secondary objectives of the trial |
• To evaluate the dose-response relationship in sitting diastolic blood pressure (msDBP) lowering of ascending doses of AHU377 in combination with valsartan 320 mg
• To evaluate changes in mean 24 hour ambulatory SBP (maSBP), mean 24 hour ambulatory DBP (maDBP), daytime and nighttime msSBP/maDBP of ascending doses of AHU377 in combination with valsartan 320mg as compared to valsartan 320mg monotherapy
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent must be obtained before any assessment is performed
2. Males and females patients, age 18 years of age and older.
3. Patients with mild-to-moderate systolic hypertension, untreated or currently taking antihypertensive therapy.
4. Untreated patients must have an office msSBP ≥ 150 mmHg and < 180 mmHg and an msDBP ≥ 70 mmHg at the randomization visit (Visit 3) and the preceding visit (Visit 2).
5. Patients who are newly diagnosed with essential hypertension or patients having a history of hypertension but who have not been taking any antihypertensive drugs (or are untreated as defined above) for at least 4 weeks prior to Visit 1
6. Pretreated patients must have an msSBP ≥ 150 mmHg and < 180 mmHg and a msDBP ≥ 70 mmHg at baseline (Visit 3)
7. Patients must have an absolute difference of ≤15 mmHg in msSBP during the last two consecutive visits (inclusive of Visit 3)
8. Ability to communicate and comply with all study requirements and demonstrate good medication compliance (≥ 80% compliance rate) during the run-in period.
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| E.4 | Principal exclusion criteria |
1. Severe hypertension (msDBP ≥110 mmHg and/or msSBP ≥ 180 mmHg).
2. History of angioedema, drug-related or otherwise, as reported by the patient.
3. Pregnant or nursing (lactating) women, where pregnancy is defined as a state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (≥ 5 mIU/ml).
4. Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods. The two methods can be a double barrier method (if accepted by local ethnics committee) or a barrier method plus a hormonal method.
• Adequate barrier methods of contraception include: diaphragm, condom (by the partner), intrauterine device (copper or hormonal), sponge or spermicide. Hormonal contraceptives include any marketed contraceptive agent that includes an estrogen and/or a progestational agent.
• Reliable contraception should be maintained throughout the study and for 7 days after the study.
• Woman are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/ml or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
5. History or evidence of a secondary form of hypertension, including but not limited to any of the following: renal parenchymal hypertension, renovascular hypertension (unilateral or bilateral renal artery stenosis), coarctation of the aorta, primary hyperaldosteronism, Cushing’s disease, pheochromocytoma, polycystic kidney disease, and drug-induced hypertension.
6. Any history of hypertensive encephalopathy, cerebrovascular accident, transient ischemic attack (TIA), myocardial infarction, coronary bypass surgery, or any percutaneous coronary intervention (PCI)
7. Current angina pectoris requiring pharmacological therapy (use of nitrates for the treatment of angina will be allowed).
8. Patients with Type 1 or Type 2 diabetes mellitus who are not well controlled based on the investigator’s clinical judgment. It is recommended that patients currently being treated for diabetes mellitus be on stable dose of antidiabetic medication for at least 4 weeks prior to Visit 1.
9. Previous or current diagnosis of heart failure (NYHA Class II-IV).
10. Clinically significant valvular heart disease at Visit 1.
11. History or current diagnosis of the following cardiac abnormalities:
• Second or third degree AV block without a pacemaker.
• Clinically significant cardiac arrhythmias including active atrial fibrillation.
• History of familial long QT syndrome or family history of torsade de pointe.
12. History of malignancy of any organ system, treated or untreated, within the past 5 years, whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin.
13. Severe liver disease such as cirrhosis or active hepatitis.
17. Any contraindication or history of hypersensitivity to any of the study drugs or to drugs with similar chemical structures.
18. Any of the following significant laboratory abnormalities:
• Serum potassium > 5.5 mEq/L at Visit 1.
• ALT or AST > 3 times the upper limit of the normal range (ULN) at Visit 1.
• MDRD eGFR < 30 ml/min/1.73m2 at Visit 1.
• Other clinically significant laboratory abnormalities, confirmed by repeat measurements, at Visit 1 (at the investigator’s discretion).
19. History of active substance abuse (including alcohol) within the past 2 years and potentially unreliable patients.
20. Patients with night-shift employment.
21. Arm circumference > 42 cm (because of ABPM assessment)
22. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer
23. Patients previously participated and/or are currently participating in a LCA696 study
24. Persons directly involved in the execution of this clinical study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint variable for this phase II study is the dose-response relationship in mean sitting systolic blood pressure (msSBP) after 8 weeks of treatment with AHU377 + valsartan 320 mg as compared to valsartan 320mg monotherapy. |
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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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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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| Last visit of the last subject |
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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