| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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 |
Part 1 -
Quantify the concentration of aliskiren, amlodipine and angiotensin II (Ang II) in interstitial fluid (microdialysis), and quantify the concentration of aliskiren, angiotensin II and renin concentration and activity in the plasma and in the tissue (biopsy) of subcutaneous fat and skeletal muscle in hypertensive patients with abdominal obesity.
Part 2 (depending on the successful results of part 1):
Compare the effects of aliskiren and amlodipine on Ang II in interstitial fluid of subcutaneous fat and skeletal muscle and on RAS biomarkers in the plasma from hypertensive patients with abdominal obesity. |
|
| E.2.2 | Secondary objectives of the trial |
Compare the effects of aliskiren and amlodipine on lipid and carbohydrate metabolism in the interstitial fluid of subcutaneous fat and skeletal muscle before and during an intravenous glucose tolerance test with insulin bolus (FSIGT).
Explore the effects of aliskiren and amlodipine on peripheral insulin sensitivity using FSGIT test in hypertensive patients with abdominal obesity.
Explore the effects of aliskiren and amlodipine on mitochondrial mass and function in subcutaneous fat and skeletal muscle (tissue biopsies) in hypertensive patients with abdominal obesity.
Explore the relationship between changes in blood pressure and in RAS biomarkers measures in plasma and in fat and skeletal muscle interstitial fluid in hypertensive patients with abdominal obesity.
Assess the safety and tolerability of aliskiren and amlodipine in hypertensive patients with abdominal obesity. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female patients 18 to 65 years of age included, with a diagnosis of
hypertension and with abdominal obesity (elevated waist circumference, ≥ 102 cm in men and ≥ 88 cm in women)
2. Systolic and diastolic blood pressure and pulse rate will be assessed after the patient has rested for at least five (5) minutes. Vital signs should be within the following ranges:
Patients with history of treated hypertension: msSBP/msDBP < 160/100 mmHg and ≥ 135/85 mmHg at baseline
Patients who are newly diagnodes (untreated): msSBP/msDBP ≥135/85 mmHg and a msSBP/msDBP< 160/100 mmHg at screening, predose, and baseline.
All blood pressure measurements at other time-points should be assessed with the patient being in sitting position, unless stated otherwise in the protocol design, and utilizing the same arm for each determination.
3. Female patients of child-bearing potential must use highly effective contraception.
Total abstinence at the discretion of the investigator in cases where the age,
career, lifestyle, or sexual orientation of the patient ensures compliance. Periodic
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods),
withdrawal and double-barrier methods are not acceptable methods of
contraception. Reliable contraception should be maintained throughout the study: the premenopausal femal subjects must be instructed not to change oral contraceptive brand or dose and the investigator must try to have the biomarker samples drawn at the same 1 to 3 days in their contraceptive package.
Postmenopausal women must have no regular menstrual bleeding for at least 1
year prior to inclusion. Postmenopausal women using hormonal replacement therapy are not allowed to take part in the study. Surgical sterilization procedures or hysterectomy must be
supported with clinical documentation made available to the sponsor noted in the
Relevant Medical History / Current Medical Conditions section of the CRF.
4. Body mass index (BMI) must be between 30 and 36. For instructions and tables
see Appendix 3.
5. Able to communicate well with the investigator, to understand and comply with the
requirements of the study. Understand and sign the written informed consent.
6. Patient information and consent forms generated by the investigator must be
approved by the sponsor prior to submission to the Ethics Committee
(EC)/Institutional Review Board (IRB). A copy of the patient information and
consent forms approved by the EC/IRB must be forwarded to the sponsor prior to
study initiation.
7. The INR (international normalized ratio) must be between the local laboratory
normal ranges. |
|
| E.4 | Principal exclusion criteria |
1. Hypertension Grade 2 (msSBP ≥ 160 and/or msDBP ≥ 100 mmHg).
2. Current treatment with three or more antihypertensive treatments.
3. Moderate to heavy smokers (use of tobacco products equivalent to >10 normal
strength cigarettes per day in the previous 3 months). Non-smokers and light
smokers (use of tobacco products equivalent to ≤10 normal strength cigarettes
per day) are permitted. Each patient will be tested for urine cotinine levels.
Patients with levels greater than 500 ng/mL will be considered moderate to heavy
smokers.
4. Type 2 and Type 1 diabetes.
5. Pregnant or nursing (lactating) women, where pregnancy is defined as the state
of a female after conception and until the termination of gestation, confirmed by a
positive hCG laboratory test (> 5 mIU/mL).
• Postmenopausal women using hormone replacement therapy.
• 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 meet
the following definition of post-menopausal: 12 months of natural spontaneous)
amenorrhea or 6 months of spontaneous amenorrhea with a plasma 17β-
estradiol concentration of <20 pg/mL and a plasma FSH level of >40 IU/L or 6
weeks post surgical bilateral oophorectomy with or without hysterectomy or are
using one or more of the following acceptable methods of contraception:
surgical sterilization (e.g., bilateral tubal ligation), hormonal contraception
(implantable, patch, oral), and double-barrier methods.
• Women using hormonal contraception that has not been at a consistent dose
for at least 3 months and is not expected to remain at this dose throughout the
study.
6. ASA treatment >1g/day or regular use of NSAIDs
7. Current of planned treatment with potent P-gp inhibitors, e.g. cyclosporin or
anti-fungal itraconazole.
8. Use of any prescription drugs within four (4) weeks prior dosing, or over-the-
counter (OTC) medication (vitamins, herbal supplements, dietary supplements)
within two (2) weeks prior to dosing. Paracetamol is acceptable, but must be
documented in the Concomitant medications / Significant non-drug therapies page
of the CRF.
9. Participation in any clinical investigation within 4 weeks prior to dosing or longer if
required by local regulations, and for any other limitation of participation based on
local regulations.
10. Donation or loss of 500 ml or more of blood within 8 weeks prior to first dosing,
or longer if required by local regulation.
11. Significant illness within two weeks prior to dosing.
12. A past medical history of clinically significant ECG abnormalities or a family history
grandparents, parents and siblings) of a prolonged QT-interval syndrome.
13. History of autonomic dysfunction (e.g. history of recurrent fainting in the recent past, orthostatic hypotension, sinus arrhythmia).
14. History of hypertensive encephalopathy or cerebrovascular accident at any time prior to Visit 1.
15. History of past cardiovascular events (e.g. myocardial infarction, unstable Angina pectoris etc...) during at least the 6 months prior to Visit 1.
16. Second or third degree heart block without a pacemaker.
17. Concurrent potentially life threatening arrhythmia or symptomatic arrhythmia.
18. History of acute or chronic bronchospastic disease (including asthma and chronic obstructive pulmonary disease, mild intermittent asthma, treated or not treated).
19. History of clinically significant drug allergy or history of atopic allergy (asthma, urticaria, eczematous dermatitis). History of hypersensitivity to any of the study drugs or to drugs belonging to the same therapeutic class (ARB´s or renin inhibitors) as the study drugs. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Pharmacodynamic assessment of concentration of aliskiren, amlodipine and RAS biomarkers in hypertensive patients with abdominal obesity.
|
|
| 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 | No |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Information not present in EudraCT |
| 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 | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 0 |
| 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 | Information not present in EudraCT |
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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