To assess the efficacy of blood pressure lowering and the safety of increasing doses of perindopril and amlodipine combination and to compare them to another validated antihypertensive strategy using valsartan and valsartan combined to amlodipine.
ID
Source
Brief title
Condition
- Vascular hypertensive disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary efficacy end point
Mean change from baseline to M3 of supine systolic BP measured at trough in the
investigator*s office using an automatic validated device.
Primary Safety End Points
* Emergent Adverse Events occurring during the double blind period of the study
(until M6)
* Leg oedema assessment by the investigator
* Clinically significant orthostatic hypotension evaluation
* Clinically significant biochemical and haematological abnormalities
Secondary outcome
Office blood pressure
Mean changes from baseline in:
- Mean Supine Diastolic blood pressure
- Controlled blood pressure
- Response rate to treatment
Definitions are provided in section 11 Efficacy measurements.
Ambulatory blood pressure monitoring
Change from baseline for the following parameters:
-mean systolic blood pressure over 24 hours (main ABPM criterion).
Tertiary end points see protocol p26
Background summary
It is estimated that hypertension affects as many as a billion people worldwide
and that each year over 7 million deaths may be attributable to hypertension.
Many large randomised intervention trials have shown that blood presssure (BP)
lowering over prolonged durations of up to 5 years, using one or more of
several drug classes is associated with large and significant reductions in all
major cardiovascular endpoints and deaths.
The most recent European and American guidelines have recommended that fixed
dose combinations of 2 drugs may be suitable as first line agents for marked
BP elevation or high risk patients.
Combination of Perindopril and Amlopdipine (P/A)
S05985, is a combination of perindopril(an ACE inhibitor) and amlodipine (a
dihydropyridine calcium channel antagonist) used in the treatment of
hypertension. Both drugs have been in common clinical use for treating
hypertension in many countries worldwide for more than 15 years.
The fixed combination is a good candidate to improve the benefit risk ratio and
to meet the recommended target BP values for more patients.
This drug combination has been developed in a single tablet form and three
possible dose combinations will be used in the trial (Perindopril
arginine/Amlodipine: 3.5/2.5; 7.0/5 and 14.0/10 mg).
Study comparator
Doses of Valsartan/Amlodipine combinations (V/A)
Valsartan (Angiotensine II Receptor Blocker) is available worldwide and
indicated for the treatment of essential hypertension.
The combination of valsartan and amlodipine is available in Europe and in many
other countries for the treatment of essential hypertension in 3 doses (80/5,
160/5, 160/10mg).
The combination and up-titration steps used in the trial are 80/0, 160/0, 160/5
and 160/10mg.
Study objective
To assess the efficacy of blood pressure lowering and the safety of increasing
doses of perindopril and amlodipine combination and to compare them to another
validated antihypertensive strategy using valsartan and valsartan combined to
amlodipine.
Study design
This is a Phase III prospective, international, multicentre, comparative
double-blind randomised versus active treatment, study.1.600 mild to moderate
hypertensive patients will be enrolled and randomised into one of the treatment
strategies. The total duration of the study treatment for the patients will be
of 14 months.
The study will be divided into following periods:
- Placebo run-in period of 2 weeks (max 4 weeks)
- M00: patients will randomly receive the starting dose of the P/A or V/A
strategy.
- M01, M02, M03: patients with uncontrolled BP will follow a titration scheme
with increasing doses step by step, of each treatment strategy until their BP
is controlled. Controlled BP is defined as systolic blood pressure (SBP) < 140
Hg and diastolic blood pressure (DBP) < 90mmHg. When controlled BP is achieved,
the patient will continue at the same dose. Patients not controlled with the
upper dose will receive indapamide 1.5mg slow-release as add on therapy or a
higher dose of the valsartan/amlodipine combination according to the treatment
strategy arm.
- M06: patients with controlled BP will enter in a open label follow-up period
for 8 months, and will only receive the P/A combination at the same step of
dose than the one reached at M6 for patients previously receiving P/A strategy
or at the equivalent or closest step of dose for patients previously receiving
V/A strategy. No up-titration will be allowed during the long-term follow-up
period. Patients whose blood pressure becomes uncontrolled during this open
label period at 2 consecutive visits or whose SBP/DBP is above 160/100 mmHg
(confirmed with 2 measurements within15 days ) will be withdrawn from the
study.
Intervention
Blood samples will be taken during the study for haematology and biochemistry
at selection (+ * GCH test, for non-menopausal women only), M3, M6, M7 (only
simplified biochemistry) and M14. Approximately 70 ml blood will be taken in
total during the whole trial.
The lab results need to be available before inclusion. An ECG will be performed
at selection, M6 and M14. In those centres equipped with ambulatory blood
pressure monitoring (ABPM) material, ABPM will be proposed to the patients
before M0, M3 and M6 visits.
Two substudies are applicable but not in all centres:
- Home blood pressure monitoring (at all visits, morning and evening, 9 days)
- Applanation tonometry at M0, M3, M6
Study burden and risks
Cfr.E2 and E9
Internationalelaan 57
B-1070 Brussel
BE
Internationalelaan 57
B-1070 Brussel
BE
Listed location countries
Age
Inclusion criteria
Selection
Patients women and men of at least 18 years with BMI*30:
For untreated patients: 150*SBP<180 mmHg and 95mmHg*DBP <110mmHg
For treated patients with no more than2 antihypertensive drugs and who in the investigator*s opinion require a change in medication either because of insufficient efficacy or poor tolerability: SBP <160 mmHg and DBP<100 mmHg.;Inclusion visit
After two weeks placebo run-in period 150*SBP<180 mmHg and 95mmHg*DBP <110mmHg
Tablet compliance *70%and* 130%during placebo period
Exclusion criteria
Selection
Patients treated with more than 2 antihypertensive drugs at the selection visit or treated with Perindopril arginine/Amlodipine or Valsartan/Amlodipine free or fixed combination at the highest available doses (P10/A 10 mg or V160/A10 mg).
History of intolerance with one or several study drugs
Contraindication for using the study drugs
History of acute episode of cerebrovascular disease, acute episode of heart disease
alcholism or drug abuse
Secondary hypertension , known symptomatic orthostatic hypotension
Pregnancy, breastfeeding or possibilty to become pregnant during the study;Inclusionvisit
Presence on the selection ECG of ventricular rhytm disorders: twisting spikes, ventricular tachycardia, ventricular extra-systoles (except for isolated occurence) or atrial fibrillation or atrial flutter or other cardiac rhytm disorders leading to important beat-to-beat variations in blood pressure
Positive orthostatic test at inclusion
Selection Laboratory result unavailable
Hyponatraemia (<135 mmol/L) or hypernatraemia (>150 mmol/L), hypokalaemia (<3.5 mmol/L) or hyperkalaemia (>5.8 mmol/L).
Creatinine clearance <30ml/min,using Cockcroft*s formula
ALAT or ASAT upper than 3 times the upper limit of normal laboratory range
Positive pregnancy test (beta GCH) performed at selection visit
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
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-020945-28-NL |
| CCMO | NL33736.018.10 |