The primary objective of this study is to determine the effects of aliskiren, as compared to ramipril, on renal hemodynamics in overweight/obese and hypertensive patients.
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
systemische en glomerulaire hypertensie
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- Renal hemodynamics (GFR, ERPF, FF)
- Blood pressure
Secondary outcome
- Volume status (extracellular fluid volume/ECV)
- RAAS parameters (plasma renin activity, plasma renin concentration,
angiotensin II, aldosteron)
- Urine en derum 'kidney injury markers', zoals, maar niet uitsluitend, TGFß,
KIM-1, NGAL en NAG.
Background summary
The combination of hypertension and obesity is a highly prevalent clustering of
cardiovascular risk factors which considerably contributes to over-all
morbidity and mortality in the general population. The kidneys play a central
role in the interaction between these two risk factors.
Obese or overweight hypertensive patients have increased glomerular pressure,
which is considered a driving force for progressive end-organ damage of the
kidney, thus contributing to the vicious circle of hypertension and target
organ damage. In line, weight excess is an independent risk factor for renal
damage that adds to the effect of elevated blood pressure. Accordingly,
specific correction of increased glomerular pressure, on top of reduction of
systemic blood pressure, has been shown to be renoprotective in experimental
animals and in renal patients. Glomerular pressure is determined by the net
balance between the tone of the afferent and efferent glomerular vessels and is
mainly regulated by the Renin Angiotensin Aldosterone System (RAAS) that
modifies efferent vascular tone. This is particularly relevant given the
availability of antihypertensive drugs that specifically interfere in the RAAS,
i.e. the ACE-inhibitors (ACEi), the Angiotensin Receptor Blockers (ARB) and
specific renin-inhibition. Based on these considerations it is likely that the
renal hemodynamic actions of RAAS-blockade will be of specific benefit in
overweight or obese hypertensive patients.
Aliskiren represents the new class of direct renin inhibitors, i.e. blockade of
the RAAS at its point of activation. Importantly, the effects of aliskiren on
glomerular pressure have not been tested so far. A beneficial short term
(decrease of glomerular pressure) and long term (prevention of end stage renal
disease) renal profile has been proven with the older RAAS blocking drug
classes (ACEi, ARB). It seems logical to assume that aliskiren will decrease
glomerular pressure as well, in particular because renin-inhibition with older
renin-inhibitors was shown to have more potent renal effects than ACEi and ARB.
In our hands renin-inhibition with remikiren was shown to reduce glomerular
pressure in hypertensive and normotensive volunteers.
Study objective
The primary objective of this study is to determine the effects of aliskiren,
as compared to ramipril, on renal hemodynamics in overweight/obese and
hypertensive patients.
Study design
The study question will be addressed in a prospective, single-centre,
double-blind, double-dummy, cross-over, randomized clinical trial. Before
inclusion, patients visit the outpatient nephrology clinic for clinical
assessment. Patients treated with antihypertensive medication will enroll in a
6 week wash-out period in which antihypertensive medication is discontinued. In
week 3 of the wash-out period, systolic and diastolic blood pressure is
measured and must remain lower than 180 and 110 mmHg, respectively. When blood
pressure exceeds these values, the patient will be considered a screen failure
and prior antihypertensive medication is restarted. A wash-out period is not
mandatory in patients with no antihypertensive medication. Consecutively,
patients will be randomly assigned to either a 6-week treatment period with
aliskiren and ramipril-placebo or a 6-week treatment period with ramipril and
aliskiren-placebo, in a cross-over double-dummy design. To safeguard patients,
serum potassium and blood pressure is measured 2 weeks after start of each
treatment period (see paragraph 7.4.1 for action to be taken when hyperkalemia
or hypotension occurs). Between both treatment periods an 8-week wash-out
period is present in which systolic and diastolic blood pressure are measured
and must remain lower than 180 and 110 mmHg, respectively. When blood pressure
exceeds these values, clonidin is started in an initial dosage of 2 dd 0.075 mg
with subsequent increase of dosage (maximal 3 dd 0.15 mg) to reach target blood
pressure. Patients visit the outpatient nephrology clinic at start and end of
both treatment periods (four times in total) for clinical assessment and renal
hemodynamic (GFR, ERPF and FF) and volume status (ECV) measurements. Renal
hemodynamics are measured by infusion of radioactive isotopes (GFR by
iothalamate; ERPF by hippuran and FF as a ratio of GFR and ERPF) and volume
status (ECV) is calculated using the distribution volume of iothalamate. A
fasting blood sample for measurement of status of the
renin-angiotensin-aldosterone system, including plasma renin activity, plasma
renin concentration, angiotensin II and aldosterone, is collected with a
venapuncture already performed for measurement of renal hemodynamics.
Additional parameters include routine blood and urine chemistry and total blood
cell count. Blood pressure is measured by an ambulant device (Spacelab) and
24hr urine is collected at the day prior to the hospital visit.
Intervention
Treatment period 1: aliskiren 1dd 300 mg and placebo ramipril (double-dummy
design)
Treatment periode 2: ramipril 1dd 10 mg and placebo aliskiren (double-dummy
design)
Treatment period is randomised
Study burden and risks
Patients visit the outpatient nephrology clinic on a more regular base than
standard patient care - i.e. at study inclusion and at start and end of each
treatment period (5 hospital visits in a total study duration of 26 weeks) -
for clinical assessment, renal hemodynamics (GFR, ERPF, FF) volume status (ECV)
measurements. Renal hemodynamics are measured by infusion of radioactive
isotopes (GFR by iothalamate; ERPF by hippuran and FF as a ratio of GFR and
ERPF) and volume status is calculated using the distribution volume of
iothalamate. A fasting blood sample is collected with a venapuncture already
performed for measurement of renal hemodynamics. Blood pressure is measured by
ambulant device (Spacelab) and 24hr urine is collected at the day prior to the
hospital visit. The amount of radioactive radiation during renal hemodynamic
measurements is comparable to a single X-thorax (less then 5% of the accepted
yearly dosage of background radiation). In this hospital, renal hemodynamic
measurements are routinely performed for daily patient care and are of minimal
risk. No other invasive measurements will be executed. There are no direct
benefits for the patients to be included and participation is on a free-will
base. Patients receive financial support of 200 euro and restitution of all
travel costs. Patients receive no priority in treatment of other diseases in
the clinic during this study.
Hanzeplein 1, postbus 30.001
9700 RB Groningen
NL
Hanzeplein 1, postbus 30.001
9700 RB Groningen
NL
Listed location countries
Age
Inclusion criteria
- Male caucasian patients
- Age >=18 and <=70 years
- Overweight or obese (BMI >=27 and <=35 kg/m2)
- Essential hypertension according to WHO-criteria (systolic and diastolic blood pressure >=140 or
>=90 mmHg, respectively)
- Normal renal function (creatinine clearance >90 ml/min/1.73m2)
- Normo- or microalbuminuria (albuminuria <=300mg/day)
- Written informed consent
Exclusion criteria
- Inability to meet inclusion criteria
- Previously treated (within 3 months prior to start of study) with aliskiren or ramipril.
- Cardiovascular disease (myocardial infarction, angina pectoris, percutanous transluminal
coronary angioplasty, coronary artery bypass grafting, stroke, heart failure (NYHA I-IV), Diabetes
Mellitus
- Active malignancy
- Any medication, surgical or medical condition which might significantly alter the absorption,
distribution, metabolism, or excretion of medications including, but not limited to any of the
following:
- History of active inflammatory bowel disease within the last six months;
- Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel
resection;
- Gastro-intestinal ulcers and/or gastrointestinal or rectal bleeding within last six months;
- Pancreatic injury or pancreatitis within the last six months;
- Evidence of hepatic disease as determined by any one of the following: ALT or AST values
exceeding 3x ULN at inclusion visit, a history of hepatic encephalopathy, a history of
esophageal varices, or a history of portocaval shunt;
- Evidence of urinary obstruction of difficulty in voiding at inclusion
- History of severe hypersensitivity or contraindications to ramipril or aliskiren
- Hypersensitivity to 125I-iothalamate or 131I-hippuran
- History of angioedema
- History of autonomic dysfunction (e.g. history of fainting or clinically significant orthostatic
hypotension)
- Participation in any clinical investigation within 3 months prior to start of the study
- Donation or loss of 400 ml or more of blood within 3 months prior to initial dosing
- History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such abuse
as indicated by the laboratory assays conducted during the screening.
- History of noncompliance to medical regimens or unwillingness to comply with the study
protocol.
- Any surgical or medical condition, which in the opinion of the investigator, may place the patient
at higher risk from his/her participation in the study, or is likely to prevent the patient from
complying with the requirements of the study or completing the study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-021987-13-NL |
| CCMO | NL33146.042.10 |
| OMON | NL-OMON28302 |